annex i summary of product characteristicsec.europa.eu/health/documents/community-register/... ·...

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

Rayzon 20 mg powder for solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

20 mg vial: Each vial contains 20 mg parecoxib (present as 21.18 mg parecoxib sodium) forreconstitution. After reconstitution, the final concentration of parecoxib is 20 mg/ml.

For excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for injectionWhite to off-white powder.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

For the short-term treatment of postoperative pain.

4.2 Posology and method of administration

The recommended dose is 40 mg administered intravenously (IV) or intramuscularly (IM),followed every 6 to 12 hours by 20 mg or 40 mg as required, not to exceed 80 mg/day. The IVbolus injection may be given rapidly and directly into a vein or into an existing IV line. The IMinjection should be given slowly and deeply into the muscle. (see section 6.6 for instructions forreconstitution)

Elderly: No dosage adjustment is generally necessary in elderly patients (≥ 65 years). However,for elderly patients weighing less than 50 kg, initiate treatment with half the usual recommendeddose of Rayzon and reduce the maximum daily dose to 40 mg (see section 5.2).

Hepatic Impairment: No dosage adjustment is generally necessary in patients with mild hepaticimpairment (Child-Pugh scale 5-6). Introduce Rayzon with caution and at half the usualrecommended dose in patients with moderate hepatic impairment (Child-Pugh scale 7-9) andreduce the maximum daily dose to 40 mg. There is no clinical experience in patients with severehepatic impairment (Child-Pugh scale > 9), therefore its use is not recommended in these patients.(see sections 4.3 and 5.2)

Renal Impairment: On the basis of pharmacokinetics, no dosage adjustment is necessary inpatients with mild to moderate (creatinine clearance of 30-80 ml/min.) or severe (creatinineclearance < 30 ml/min.) renal impairment. However, caution should be observed in patients withrenal impairment or patients who may be predisposed to fluid retention. (see sections 4.4 and 5.2)

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Children and adolescents: Rayzon has not been studied in patients under 18 years. Therefore, itsuse is not recommended in these patients.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. (see section 6.1).

Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema,urticaria or allergic-type reactions after taking acetylsalicylic acid or NSAIDs or othercyclooxygenase-2 (COX-2) selective inhibitors.

The third trimester of pregnancy and breast-feeding. (see sections 4.6 and 5.3)

Severe hepatic impairment (Child-Pugh > 9).

Active peptic ulceration or gastrointestinal bleeding.

Inflammatory bowel disease.

Severe congestive heart failure.

4.4 Special warnings and special precautions for use

There is limited clinical experience with Rayzon treatment beyond two days.

Rayzon has been studied in dental, orthopaedic, gynaecologic (principally hysterectomy) andcoronary artery bypass graft surgery. There is little experience in other types of surgery, forexample gastrointestinal or urological surgery.

Rayzon should be used with caution to treat pain following coronary artery bypass graft surgeryas these patients may have a higher risk of adverse events, such as cerebrovascular accident, renaldysfunction or sternal wound complication (infection, dehiscence), especially those with a historyof cerebrovascular disease or with a body mass index > 30 kg/m2. (see section 4.8)

Since prostaglandin synthesis inhibition may result in deterioration of renal function and fluidretention, caution should be observed when administering Rayzon in patients with impaired renalfunction (see section 4.2) or hypertension, or in patients with compromised cardiac or hepaticfunction or other conditions predisposing to fluid retention.

Caution should be used when initiating treatment with Rayzon in patients with dehydration. Inthis case, it is advisable to rehydrate patients first and then start therapy with Rayzon.

Rayzon should be used with caution in patients with moderate hepatic impairment (Child-Pugh 7-9). (see section 4.2)

Rayzon may mask fever. (see section 5.1) In isolated cases, an aggravation of soft tissueinfections has been described in connection with the use of NSAIDs and in nonclinical studieswith Rayzon. (see section 5.3) Caution should be exercised with respect to monitoring theincision for signs of infection in surgical patients receiving Rayzon.

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Upper gastrointestinal perforations, ulcers or bleeds (PUBs) have occurred in patients treated withRayzon. Therefore, caution should be taken in patients with a history of PUBs.

Because of its lack of effect on platelets, Rayzon is not a substitute for acetylsalicylic acid forcardiovascular prophylaxis.

Caution should be exercised when co-administering Rayzon with warfarin. (see section 4.5)

The use of Rayzon, as with any medicinal product known to inhibit COX-2, is not recommendedin women attempting to conceive. (see sections 4.6 and 5.1)

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactionsAnticoagulant therapy should be monitored, particularly during the first few days after initiatingRayzon therapy in patients receiving warfarin or similar agents, since these patients have anincreased risk of bleeding complications.

Rayzon had no effect on acetylsalicylic acid-mediated inhibition of platelet aggregation orbleeding times. Clinical trials indicate that Rayzon can be given with low dose acetylsalicylicacid ( � 325 mg).

Co-administration of parecoxib sodium and heparin did not affect the pharmacodynamics ofheparin (activated partial thromboplastin time) compared to heparin alone.

NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. As forNSAIDs, the risk of acute renal insufficiency may be increased when ACE inhibitors or diureticsare co-administered with parecoxib sodium.

Co-administration of NSAIDs and cyclosporin or tacrolimus has been suggested to increase thenephrotoxic effect of cyclosporin and tacrolimus. Renal function should be monitored whenparecoxib sodium and any of these medicinal products are co-administered.

Rayzon may be co-administered with opioid analgesics. When Rayzon was co-administered withmorphine, a smaller dose (by 28-36%) of morphine could be used to achieve the same clinicallevel of analgesia.

Effects of other medicinal products on the pharmacokinetics of parecoxib (or its active metabolitevaldecoxib)Parecoxib is rapidly hydrolysed to the active metabolite valdecoxib. In humans, studiesdemonstrated that valdecoxib metabolism is predominantly mediated via CYP3A4 and 2C9isozymes.

Plasma exposure (AUC and Cmax) to valdecoxib was increased (62% and 19%, respectively) whenco-administered with fluconazole (predominantly a CYP2C9 inhibitor), indicating that the doseof parecoxib sodium should be reduced in those patients who are receiving fluconazole therapy.

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Plasma exposure (AUC and Cmax) to valdecoxib was increased (38% and 24%, respectively) whenco-administered with ketoconazole (CYP3A4 inhibitor), however, a dosage adjustment should notgenerally be necessary for patients receiving ketoconazole.

The effect of enzyme induction has not been studied. The metabolism of valdecoxib mayincrease when co-administered with enzyme inducers such as rifampicin, phenytoin,carbamazepine ordexamethasone.

Effect of parecoxib (or its active metabolite valdecoxib) on the pharmacokinetics of othermedicinal productsTreatment with valdecoxib (40 mg twice daily for 7 days) produced a 3-fold increase in plasmaconcentrations of dextromethorphan (CYP2D6 substrate). Therefore, caution should be observedwhen co-administering Rayzon and medicinal products that are predominantly metabolised byCYP2D6 and which have narrow therapeutic margins (e.g. flecainide, propafenone, metoprolol).

Plasma exposure of omeprazole (CYP 2C19 substrate) 40 mg once daily was increased by 46%following administration of valdecoxib 40 mg twice daily for 7 days, while the plasma exposureto valdecoxib was unaffected. These results indicate that although valdecoxib is not metabolisedby CYP2C19, it may be an inhibitor of this isoenzyme. Therefore, caution should be observedwhen administering Rayzon with medicinal products known to be substrates of CYP2C19 (e.g.phenytoin, diazepam, or imipramine).

In interaction studies in rheumatoid arthritis patients receiving weekly methotrexateintramuscularly, orally administered valdecoxib (40 mg twice daily) did not have a clinicallysignificant effect on the plasma concentrations of methotrexate. However, adequate monitoring ofmethotrexate-related toxicity should be considered when co-administering these two medicinalproducts.

Co-administration of valdecoxib and lithium produced significant decreases in lithium serumclearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared tolithium alone. Lithium serum concentration should be monitored closely when initiating orchanging parecoxib sodium therapy in patients receiving lithium.

Co-administration of valdecoxib with glibenclamide (CYP3A4 substrate) did not affect either thepharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) ofglibenclamide.

Injectable anaesthetics: Coadministration of IV parecoxib sodium 40 mg with propofol(CYP2C9 substrate) or midazolam (CYP3A4 substrate) did not affect either the pharmacokinetics(metabolism and exposure) or the pharmacodynamics (EEG effects, psychomotor tests andwaking from sedation) of IV propofol or IV midazolam. Additionally, coadministration ofvaldecoxib had no clinically significant effect on the hepatic or intestinal CYP 3A4-mediatedmetabolism of orally administered midazolam. Administration of IV parecoxib sodium 40 mghad no significant effect on the pharmacokinetics of either IV fentanyl or IV alfentanil (CYP3A4substrates).

Inhalation anaesthetics: No formal interaction studies have been done. In surgery studies inwhich parecoxib sodium was administered pre-operatively, no evidence of pharmacodynamic

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interaction was observed in patients receiving parecoxib sodium and the inhalation anaestheticagents nitrous oxide and isoflurane. (see section 5.1)

4.6 Pregnancy and lactation

Pregnancy:The use of Rayzon is contraindicated in the last trimester of pregnancy because as with othermedicinal products known to inhibit prostaglandin synthesis, it may cause premature closure ofthe ductus arteriosus or uterine inertia. (see sections 4.3, 5.1 and 5.3)

Like other medicinal products that inhibit COX-2, Rayzon is not recommended in womenattempting to conceive. (see sections 4.4, 5.1 and 5.3)

There are no adequate data from the use of parecoxib sodium in pregnant women or duringlabour. Studies in animals have shown reproductive effects (see sections 5.1 and 5.3). Thepotential risk for humans is unknown. Rayzon should not be used during the first two trimestersof pregnancy or labour unless the potential benefit to the patient outweighs the potential risk tothe foetus.

Lactation:Parecoxib, valdecoxib (its active metabolite) and a valdecoxib active metabolite are excreted inthe milk of rats. It is not known whether valdecoxib is excreted in human milk. Rayzon shouldnot be administered to women who breast-feed. (see sections 4.3 and 5.3)

4.7 Effects on ability to drive and use machines

No studies on the effect of Rayzon on the ability to drive or use machines have been performed.However, patients who experience dizziness, vertigo or somnolence after receiving Rayzonshould refrain from driving or operating machines.

4.8 Undesirable effects

Of the Rayzon treated patients in controlled trials, 1962 were patients with post-surgical pain.

The following undesirable effects had a rate greater than placebo and have been reported among1543 patients administered Rayzon 20 or 40 mg as a single or multiple dose (up to 80 mg/day) in12 placebo controlled studies, including dental, gynaecologic, orthopaedic surgery or coronaryartery bypass graft surgery as well as pre-operative administration in dental and orthopaedicsurgeries. The discontinuation rate due to adverse events in these studies was 5.0 % for patientsreceiving Rayzon and 4.3% for patients receiving placebo.

Common ( > 1/100, <1/10)Autonomic Nervous System Disorders: hypertension, hypotension.Body as a Whole - General Disorders: back pain, peripheral oedema.Central and Peripheral Nervous System Disorders: hypoaesthesia.Gastro-intestinal System Disorders: alveolar osteitis (dry socket), dyspepsia, flatulence.Metabolic and Nutritional Disorders: creatinine increase, hypokalaemiaPsychiatric Disorders: agitation, insomnia.Red Blood Cell Disorders: post-operative anaemia

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Respiratory Disorders: pharyngitis, respiratory insufficiency.Skin and Appendages Disorders: pruritus.Urinary System Disorders: oliguria.

Uncommon ( >1/1,000, <1/100)Autonomic Nervous System Disorders: aggravated hypertension.Body as a Whole - General Disorders: abnormal sternal serous wound drainage, woundinfection.Gastro-intestinal System Disorders: gastroduodenal ulcerationHeart Rate and Rhythm Disorders: bradycardia.Liver and Biliary System Disorders: SGOT increased, SGPT increased.Metabolic and Nutritional Disorders: BUN increased.Platelet, Bleeding and Clotting disorders: ecchymosis, thrombocytopeniaVascular (Extracardiac) Disorders: cerebrovascular disorder.

The following rare, serious adverse events have been reported in association with the use ofNSAIDs and cannot be ruled out for Rayzon: acute renal failure, congestive heart failure,anaphylactic shock, bronchospasm, hepatitis.

Following coronary artery bypass graft surgery, patients administered Rayzon may have a higherrisk of adverse events, such as cerebrovascular accident, renal dysfunction or sternal woundcomplication.

4.9 Overdose

No case of parecoxib overdose has been reported.

In case of overdose, patients should be managed by symptomatic and supportive care.Valdecoxib is not removed by haemodialysis. Diuresis or alkalisation of urine may not be usefuldue to high protein binding of valdecoxib.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Coxib, ATC code: M01AH

Parecoxib is a prodrug of valdecoxib. The mechanism of action of valdecoxib is by inhibition ofcyclooxygenase-2 (COX-2)-mediated prostaglandin synthesis. Cyclooxygenase is responsible forgeneration of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 isthe isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli andhas been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain,inflammation, and fever. At therapeutic doses, valdecoxib is a COX-2 selective inhibitor of bothperipheral and central prostaglandins and does not inhibit COX-1, thereby sparing COX-1dependent physiological processes in tissues, particularly the stomach, intestine and platelets.COX-2 is also thought to be involved in ovulation, implantation and closure of the ductusarteriosus, and central nervous system functions (fever induction, pain perception and cognitivefunction).

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The efficacy of Rayzon was established in studies of dental, gynaecologic (hysterectomy),orthopaedic (knee and hip replacement), and coronary artery bypass graft surgical pain. The firstperceptible analgesic effect occurred in 7 -13 minutes, with clinically meaningful analgesiademonstrated in 23-39 minutes and a peak effect within 2 hours following administration ofsingle doses of 40 mg IV or IM Rayzon. The magnitude of analgesic effect of the 40 mg dose wascomparable with that of ketorolac 60 mg IM or ketorolac 30 mg IV. After a single dose, theduration of analgesia was dose and clinical pain model dependent, and ranged from 6 to greaterthan 12 hours.

Gastrointestinal studies: In short-term studies (7 days), the incidence of endoscopically observedgastroduodenal ulcers or erosions in healthy young and elderly (� 65 years) subjects administeredRayzon (5-21%), although higher than placebo (5-12%), was statistically significantly lower thanthe incidence observed with NSAIDs (66-90%).

Platelet studies: In a series of small, multiple dose studies in healthy young and elderly subjects,Rayzon 20 mg or 40 mg twice daily had no effect on platelet aggregationor bleeding compared to placebo. In young subjects, Rayzon 40 mg twice daily had no clinicallysignificant effect on aspirin-mediated inhibition of platelet function. (see section 4.5)

5.2 Pharmacokinetic properties

Following IV or IM injection, parecoxib is rapidly converted to valdecoxib, thepharmacologically active substance, by enzymatic hydrolysis in the liver.

AbsorptionExposure of valdecoxib following single doses of Rayzon, as measured by both the area under theplasma concentration vs. time curve (AUC) and peak concentration (Cmax), is approximatelylinear in the range of clinical doses. AUC and Cmax following twice daily administration is linearup to 50 mg IV and 20 mg IM. Steady state plasma concentrations of valdecoxib were reachedwithin 4 days with twice daily dosing.

Following single IV and IM doses of parecoxib sodium 20 mg, Cmax of valdecoxib is achieved inapproximately 30 minutes and approximately 1 hour, respectively. Exposure to valdecoxib wassimilar in terms of AUC and Cmax following IV and IM administration. Exposure to parecoxibwas similar after IV or IM administration in terms of AUC. Average Cmax of parecoxib after IMdosing was lower compared to bolus IV dosing, which is attributed to slower extravascularabsorption after IM administration. These decreases were not considered clinically importantsince Cmax of valdecoxib is comparable after IM and IV parecoxib sodium administration.

DistributionThe volume of distribution of valdecoxib after its IV administration is approximately 55 liters.Plasma protein binding is approximately 98% over the concentration range achieved with thehighest recommended dose, 80 mg/day. Valdecoxib, but not parecoxib, is extensively partitionedinto erythrocytes.

MetabolismParecoxib is rapidly and almost completely converted to valdecoxib and propionic acid in vivowith a plasma half-life of approximately 22 minutes. Elimination of valdecoxib is by extensive

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hepatic metabolism involving multiple pathways, including cytochrome P 450 (CYP) 3A4 andCYP2C9 isoenzymes and glucuronidation (about 20%) of the sulphonamide moiety. Ahydroxylated metabolite of valdecoxib (via the CYP pathway) has been identified in humanplasma that is active as a COX-2 inhibitor. It represents approximately 10% of the concentrationof valdecoxib; because of this metabolite’s low concentration, it is not expected to contribute asignificant clinical effect after administration of therapeutic doses of parecoxib sodium.

EliminationValdecoxib is eliminated via hepatic metabolism with less than 5% unchanged valdecoxibrecovered in the urine. No unchanged parecoxib is detected in urine and only trace amounts inthe faeces. About 70% of the dose is excreted in the urine as inactive metabolites. Plasmaclearance (CLp) for valdecoxib is about 6 l/hr. After IV or IM dosing of parecoxib sodium, theelimination half-life (t1/2) of valdecoxib is about 8 hours.

Elderly Subjects: Rayzon has been administered to 335 elderly patients (65-96 years of age) inpharmacokinetic and therapeutic trials. In healthy elderly subjects, the apparent oral clearance ofvaldecoxib was reduced, resulting in an approximately 40% higher plasma exposure ofvaldecoxib compared to healthy young subjects. When adjusted for body weight, steady stateplasma exposure of valdecoxib was 16% higher in elderly females compared to elderly males.(see section 4.2)

Renal Impairment: In patients with varying degrees of renal impairment administered 20 mgIVRayzon, parecoxib was rapidly cleared from plasma. Because renal elimination of valdecoxibis not important to its disposition, no changes in valdecoxib clearance were found even in patientswith severe renal impairment or in patients undergoing dialysis. (see section 4.2)

Hepatic Impairment: Moderate hepatic impairment did not result in a reduced rate or extent ofparecoxib conversion to valdecoxib. In patients with moderate hepatic impairment (Child-Pughscale 7-9), treatment should be initiated with half the usual recommended dose of Rayzon and themaximum daily dose should be reduced to 40 mg since valdecoxib exposures were more thandoubled (130%) in these patients. Patients with severe hepatic impairment have not been studiedand therefore the use of Rayzon in patients with severe hepatic impairment is not recommended.(see sections 4.2 and 4.3)

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology or repeated dose toxicity at 2-fold the maximum human exposure to parecoxib.However, in the repeated dose toxicity studies in dogs and rats, the systemic exposures tovaldecoxib (the active metabolite of parecoxib) were approximately 0.8-fold the systemicexposure in elderly human subjects at the maximum recommended therapeutic dose of 80 mgdaily. Higher doses were associated with aggravation and delayed healing of skin infections, aneffect probably associated with COX-2 inhibition.

In reproduction toxicity tests, the incidence of post-implantation losses, resorptions and foetalbody weight retardation occurred at doses not producing maternal toxicity in the rabbit studies.No effects of parecoxib on male or female fertilities were found in rats.

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The effects of parecoxib have not been evaluated in late pregnancy or in the pre- and postnatalperiod.Parecoxib sodium administered intravenously to lactating rats as a single dose showedconcentrations of parecoxib, valdecoxib and a valdecoxib active metabolite in milk similar to thatof maternal plasma.

The carcinogenic potential of parecoxib sodium has not been evaluated.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

PowderDibasic sodium phosphate, heptahydratePhosphoric acid and/or sodium hydroxide (for pH adjustment).

20 mg vial: When reconstituted in sodium chloride 9 mg/ml (0.9%) solution, Rayzon containsapproximately 0.22 mEq of sodium per vial.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products other than thosementioned in 6.6.

Rayzon and opioids should not be administered together in the same syringe.

Use of Ringer-Lactate solution for injection or glucose 50 g/l (5%) in Ringer Lactate solution forinjection for reconstitution will cause the parecoxib to precipitate from solution and therefore isnot recommended.

Use of Sterile Water for Injection is not recommended, as the resulting solution is not isotonic.

Injection into an IV line delivering glucose 50 g/l (5%) in Ringer-Lactate solution for injection,or other IV fluids not listed in 6.6, is not recommended as this may cause precipitation fromsolution.

6.3 Shelf life

3 years.

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24hours at 25�C. From a microbiological point of view, the aseptically prepared product should beused immediately. If not used immediately, in-use storage times and conditions prior to use arethe responsibility of the user and would not normally be longer than 12 hours at 25�C, unlessreconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

No special precautions for storage prior to reconstitution.

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Do not refrigerate or freeze reconstituted solutions.

6.5 Nature and contents of container

Parecoxib sodium vials20 mg vials: Type I colourless glass vials (2 ml) with a laminated stopper, sealed with a yellowflip-off cap on the aluminium overseal.

Rayzon is available in packs containing 10 vials.

6.6 Instructions for use and handling <and disposal>

Acceptable solvents for reconstitution of Rayzon are:

sodium chloride 9 mg/ml (0.9%) solutionglucose 50 g/l (5%) solution for infusionsodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection

Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium). Removethe yellow flip-off cap to expose the central portion of the rubber stopper of the 20 mg parecoxibvial. Withdraw, with a sterile needle and syringe, 1 ml of an acceptable solvent and insert theneedle through the central portion of the rubber stopper transferring the solvent into the 20 mgvial. Dissolve the powder completely using a gentle swirling motion and inspect the reconstitutedproduct before use. The entire contents of the vial should be withdrawn for a singleadministration.

The reconstituted solution is clear and colourless. It should be inspected visually for particulatematter and discoloration prior to administration. The solution should not be used if discolouredor cloudy or if particulate matter is observed.

The reconstituted product is isotonic.

After reconstitution with acceptable solvents, Rayzon may only be injected IV or IM, or into IVlines delivering:

sodium chloride 9 mg/ml (0.9%) solutionglucose 50 g/l (5%) solution for infusionsodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injectionRinger-Lactate solution for injection

For single use only. Any unused solution, solvent or waste material should be disposed ofaccording to local requirements.

7. MARKETING AUTHORISATION HOLDER

Pharmacia Europe EEIGHillbottom Road

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High WycombeBuckinghamshireHP12 4PXUnited Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

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Rayzon 20 mg Powder and solvent for solution for injection





Powder and solvent for solution for injection.White to off-white powder.

Solvent: clear, colourless solution.








Renal Impairment: On the basis of pharmacokinetics, no dosage adjustment is necessary inpatients with mild to moderate (creatinine clearance of 30-80 ml/min.) or severe (creatinine

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clearance < 30 ml/min.) renal impairment. However, caution should be observed in patients withrenal impairment or patients who may be predisposed to fluid retention. (see sections 4.4 and 5.2)

















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Injectable anaesthetics: Coadministration of IV parecoxib sodium 40 mg with propofol(CYP2C9 substrate) or midazolam (CYP3A4 substrate) did not affect either the pharmacokinetics(metabolism and exposure) or the pharmacodynamics (EEG effects, psychomotor tests andwaking from sedation) of IV propofol or IV midazolam. Additionally, coadministration ofvaldecoxib had no clinically significant effect on the hepatic or intestinal CYP 3A4-mediatedmetabolism of orally administered midazolam. Administration of IV parecoxib sodium 40 mg

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had no significant effect on the pharmacokinetics of either IV fentanyl or IV alfentanil (CYP3A4substrates).

Inhalation anaesthetics: No formal interaction studies have been done. In surgery studies inwhich parecoxib sodium was administered pre-operatively, no evidence of pharmacodynamicinteraction was observed in patients receiving parecoxib sodium and the inhalation anaestheticagents nitrous oxide and isoflurane. (see section 5.1)











Common ( > 1/100, <1/10)Autonomic Nervous System Disorders: hypertension, hypotension.Body as a Whole - General Disorders: back pain, peripheral oedema.

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Central and Peripheral Nervous System Disorders: hypoaesthesia.Gastro-intestinal System Disorders: alveolar osteitis (dry socket), dyspepsia, flatulence.Metabolic and Nutritional Disorders: creatinine increase, hypokalaemiaPsychiatric Disorders: agitation, insomnia.Red Blood Cell Disorders: post-operative anaemiaRespiratory Disorders: pharyngitis, respiratory insufficiency.Skin and Appendages Disorders: pruritus.Urinary System Disorders: oliguria.




4.9 Overdose






Parecoxib is a prodrug of valdecoxib. The mechanism of action of valdecoxib is by inhibition ofcyclooxygenase-2 (COX-2)-mediated prostaglandin synthesis. Cyclooxygenase is responsible forgeneration of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 isthe isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli andhas been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain,inflammation, and fever. At therapeutic doses, valdecoxib is a COX-2 selective inhibitor of both

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peripheral and central prostaglandins and does not inhibit COX-1, thereby sparing COX-1dependent physiological processes in tissues, particularly the stomach, intestine and platelets.COX-2 is also thought to be involved in ovulation, implantation and closure of the ductusarteriosus, and central nervous system functions (fever induction, pain perception and cognitivefunction).








DistributionThe volume of distribution of valdecoxib after its IV administration is approximately 55 liters.Plasma protein binding is approximately 98% over the concentration range achieved with the

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highest recommended dose, 80 mg/day. Valdecoxib, but not parecoxib, is extensively partitionedinto erythrocytes.

MetabolismParecoxib is rapidly and almost completely converted to valdecoxib and propionic acid in vivowith a plasma half-life of approximately 22 minutes. Elimination of valdecoxib is by extensivehepatic metabolism involving multiple pathways, including cytochrome P 450 (CYP) 3A4 andCYP2C9 isoenzymes and glucuronidation (about 20%) of the sulphonamide moiety. Ahydroxylated metabolite of valdecoxib (via the CYP pathway) has been identified in humanplasma that is active as a COX-2 inhibitor. It represents approximately 10% of the concentrationof valdecoxib; because of this metabolite’s low concentration, it is not expected to contribute asignificant clinical effect after administration of therapeutic doses of parecoxib sodium.



Renal Impairment: In patients with varying degrees of renal impairment administered 20 mg IVRayzon, parecoxib was rapidly cleared from plasma. Because renal elimination of valdecoxib isnot important to its disposition, no changes in valdecoxib clearance were found even in patientswith severe renal impairment or in patients undergoing dialysis. (see section 4.2)




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The effects of parecoxib have not been evaluated in late pregnancy or in the pre- and postnatalperiod.

Parecoxib sodium administered intravenously to lactating rats as a single dose showedconcentrations of parecoxib, valdecoxib and a valdecoxib active metabolite in milk similar to thatof maternal plasma.





SolventSodium chlorideHydrochloric acid or sodium hydroxide (for pH adjustment)Water for injections.





Use of Ringer-Lactate solution for injection or glucose 50 g/l (5%) in Ringer-Lactate solution forinjection for reconstitution will cause the parecoxib to precipitate from solution and therefore isnot recommended.



6.3 Shelf life

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3 years.






Parecoxib sodium vials20 mg vials: Type I colourless glass vials (2 ml) with a laminated stopper, sealed with a yellowflip-off cap on the aluminium overseal.

Solvent ampoules2 ml ampoule: colourless neutral glass, Type I.

Rayzon is supplied as a sterile, single unit-of-use vial that is packaged with a 2 ml ampoule with afill volume of 1 ml sodium chloride 9 mg/ml (0.9%) solution (see below for various pack sizesand configurations).

Pack sizes1 x 1 pack: contains 1 vial with parecoxib 20 mg and 1 ampoule with 1 ml sodium chloride 9mg/ml (0.9%) solution.3 x 3 pack: contains 3 vials of parecoxib 20 mg and 3 ampoule with 1 ml sodium chloride 9mg/ml (0.9%) solution.5 x 5 pack: contains 5 vials of parecoxib 20 mg and 5 ampoules with 1 ml sodium chloride 9mg/ml (0.9%) solution.

Not all pack sizes may be marketed.

6.6 Instructions for use and handling and disposal

Reconstitute Rayzon 20 mg with 1 ml sodium chloride 9 mg/ml (0.9%) solution using aseptictechnique. The only other acceptable solvents for reconstitution are:

glucose 50 g/l (5%) solution for infusionsodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection

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Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium). Removethe yellow flip-off cap to expose the central portion of the rubber stopper of the 20 mg parecoxibvial. Withdraw, with a sterile needle and syringe, 1 ml of an acceptable solvent and insert theneedle through the central portion of the rubber stopper transferring the solvent into the 20 mgvial. Dissolve the powder completely using a gentle swirling motion and inspect the reconstitutedproduct before use. The entire contents of the vial should be withdrawn for a singleadministration.







Pharmacia Europe EEIGHillbottom RoadHigh WycombeBuckinghamshireHP12 4PXUnited Kingdom




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Rayzon 40 mg powder for solution for injection





Powder for solution for injectionWhite to off-white powder.








Renal Impairment: On the basis of pharmacokinetics, no dosage adjustment is necessary inpatients with mild to moderate (creatinine clearance of 30-80 ml/min.) or severe (creatinineclearance < 30 ml/min.) renal impairment. However, caution should be observed in patients withrenal impairment or patients who may be predisposed to fluid retention. (see sections 4.4 and 5.2)

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No studies on the effect of Rayzon on the ability to drive or use machines have been performed.However, patients who experience dizziness, vertigo or somnolence after receiving Rayzonshould refrain from driving or operating machines.4.8 Undesirable effects



Common ( > 1/100, <1/10)Autonomic Nervous System Disorders: hypertension, hypotension.Body as a Whole - General Disorders: back pain, peripheral oedema.Central and Peripheral Nervous System Disorders: hypoaesthesia.Gastro-intestinal System Disorders: alveolar osteitis (dry socket), dyspepsia, flatulence.Metabolic and Nutritional Disorders: creatinine increase, hypokalaemiaPsychiatric Disorders: agitation, insomnia.Red Blood Cell Disorders: post-operative anaemiaRespiratory Disorders: pharyngitis, respiratory insufficiency.Skin and Appendages Disorders: pruritus.Urinary System Disorders: oliguria.

Uncommon ( >1/1,000, <1/100)

30

Autonomic Nervous System Disorders: aggravated hypertension.Body as a Whole - General Disorders: abnormal sternal serous wound drainage, woundinfection.Gastro-intestinal System Disorders: gastroduodenal ulcerationHeart Rate and Rhythm Disorders: bradycardia.Liver and Biliary System Disorders: SGOT increased, SGPT increased.Metabolic and Nutritional Disorders: BUN increased.Platelet, Bleeding and Clotting disorders: ecchymosis, thrombocytopeniaVascular (Extracardiac) Disorders: cerebrovascular disorder.



31

4.9 Overdose











32








33






The effects of parecoxib have not been evaluated in late pregnancy or in the pre- and postnatalperiod.Parecoxib sodium administered intravenously to lactating rats as a single dose showedconcentrations of parecoxib, valdecoxib and a valdecoxib active metabolite in milk similar to thatof maternal plasma.







34






35

6.3 Shelf life

3 years.




Do not refrigerate or freeze reconstituted product.


Parecoxib sodium vials40 mg vials: Type I colourless glass vials (5 ml) with a laminated stopper, sealed with a purpleflip-off cap on the aluminium overseal.

Rayzon is available in packs containing 10 vials.6.6 Instructions for use and handling and disposal

Acceptable solvents for reconstitution of Rayzon are:

sodium chloride 9 mg/ml (0.9%) solutionglucose 50 g/l (5%) solution for infusionsodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection

Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium). Removethe purple flip-off cap to expose the central portion of the rubber stopper of the 40 mg parecoxibvial. Withdraw, with a sterile needle and syringe, 2 ml of an acceptable solvent and insert theneedle through the central portion of the rubber stopper transferring the solvent into the 40 mgvial. Dissolve the powder completely using a gentle swirling motion and inspect the reconstitutedproduct before use. The entire contents of the vial should be withdrawn for a singleadministration.




sodium chloride 9 mg/ml (0.9%) solution

36

glucose 50 g/l (5%) solution for infusionsodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injectionRinger-Lactate solution for injection

For single use only. Any unused solution, solvent or waste material should be disposed ofaccording to local requirements.7. MARKETING AUTHORISATION HOLDER





37


Rayzon 40 mg Powder and solvent for solution for injection





Powder and solvent for solution for injection.White to off-white powder.

Solvent: clear, colourless solution.








Renal Impairment: On the basis of pharmacokinetics, no dosage adjustment is necessary inpatients with mild to moderate (creatinine clearance of 30-80 ml/min.) or severe (creatinine

38

clearance < 30 ml/min.) renal impairment. However, caution should be observed in patients withrenal impairment or patients who may be predisposed to fluid retention. (see sections 4.4 and 5.2)


39


















40














41










42










Common ( > 1/100, <1/10)Autonomic Nervous System Disorders: hypertension, hypotension.Body as a Whole - General Disorders: back pain, peripheral oedema.Central and Peripheral Nervous System Disorders: hypoaesthesia.Gastro-intestinal System Disorders: alveolar osteitis (dry socket), dyspepsia, flatulence.Metabolic and Nutritional Disorders: creatinine increase, hypokalaemiaPsychiatric Disorders: agitation, insomnia.Red Blood Cell Disorders: post-operative anaemiaRespiratory Disorders: pharyngitis, respiratory insufficiency.Skin and Appendages Disorders: pruritus.Urinary System Disorders: oliguria.

43




44

4.9 Overdose











45








46






The effects of parecoxib have not been evaluated in late pregnancy or in the pre- and postnatalperiod.

Parecoxib sodium administered intravenously to lactating rats as a single dose showedconcentrations of parecoxib, valdecoxib and a valdecoxib active metabolite in milk similar to thatof maternal plasma.





SolventSodium chlorideHydrochloric acid or sodium hydroxide (for pH adjustment)Water for injections.

47







Injection into an IV line delivering Glucose 50 g/l (5%) in Ringer-Lactate solution, or other IVfluids not listed in 6.6, is not recommended as this may cause precipitation from solution.

6.3 Shelf life

3 years.






Parecoxib sodium vials40 mg vials: Type I colourless glass vials (5ml) with a laminated stopper, sealed with a purpleflip-off cap on the aluminium overseal.

Solvent ampoules2 ml ampoule: colourless neutral glass, Type I.

Rayzon is supplied as a sterile, single unit-of-use vial that is packaged with a 2 ml ampoule with afill volume of 2 ml sodium chloride 9 mg/ml (0.9%) solution (see below for various pack sizesand configurations).

48

Pack sizes1 x 1 pack: contains 1 vial with parecoxib 40 mg and 1 ampoule with 2 ml sodium chloride 9mg/ml (0.9%) solution.3 x 3 pack: contains 3 vials of parecoxib 40 mg and 3 ampoule with 2 ml sodium chloride 9mg/ml (0.9%) solution.5 x 5 pack: contains 5 vials of parecoxib 40 mg and 5 ampoules with 2 ml sodium chloride 9mg/ml (0.9%) solution.

Not all pack sizes may be marketed.

6.6 Instructions for use and handling and disposal

Reconstitute Rayzon 40 mg with 2 ml sodium chloride 9 mg/ml (0.9%) solution using aseptictechnique. The only other acceptable solvents for reconstitution are:

glucose 50 g/l (5%) solution for infusionsodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection

Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium). Removethe purple flip-off cap to expose the central portion of the rubber stopper of the 40 mg parecoxibvial. Withdraw, with a sterile needle and syringe, 2 ml of an acceptable solvent and insert theneedle through the central portion of the rubber stopper transferring the solvent into the 40 mgvial. Dissolve the powder completely using a gentle swirling motion and inspect the reconstitutedproduct before use. The entire contents of the vial should be withdrawn for a singleadministration.







Pharmacia Europe EEIGHillbottom RoadHigh Wycombe

49

BuckinghamshireHP12 4PXUnited Kingdom




50

ANNEX II

A. MANUFACTURING AUTHORISATION HOLDERRESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING

AUTHORISATION

51

A MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCHRELEASE

Name and address of the manufacturer responsible for batch release Pharmacia Ltd. Whalton Road Morpeth Northumberland NE61 3YA United Kingdom B CONDITIONS OF THE MARKETING AUTHORISATION

� CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSEDON THE MARKETING AUTHORISATION HOLDER

Medicinal product subject to medical prescription � OTHER CONDITIONS

The holder of this marketing authorisation must inform the European Commission about themarketing plans for the medicinal product authorised by this decision.

52

ANNEX III

LABELLING AND PACKAGE LEAFLET

53

A. LABELLING

54

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NOOUTER PACKAGING, ON THE IMMEDIATE PACKAGING

OUTER CARTON: 20 mgPACK SIZE: 10 vials


Rayzon 20 mg

Powder for solution for injection

Parecoxib (as parecoxib sodium)

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 20 mg parecoxib, as 21.18 mg parecoxib sodium. When reconstituted with 1ml solvent, provides 20 mg/ml of parecoxib.

3. LIST OF EXCIPIENTS

Also contains dibasic sodium phosphate heptahydrate, phosphoric acid and sodium hydroxide.

4. PHARMACEUTICAL FORM AND CONTENTS


10 vials

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use. Intravenous or intramuscular use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUTOF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

55

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

There are no special storage precautions.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTSOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IFAPPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER



EU/0/00/000/000

13. MANUFACTURER’S BATCH NUMBER

<Batch>/<Lot>{number}

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

For single use only. After reconstitution the product should be used immediately.

56

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL TEXT: 20 mg

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Rayzon 20 mg



IV/IM

2. METHOD OF ADMINISTRATION

Read the package leaflet before use.

3. EXPIRY DATE

<EXP {MM/YYYY}>

4. BATCH NUMBER

<Batch>/<Lot> <BN>

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

57


OUTER CARTON: 20 mgPACK SIZE: 1 vial AND 1 solvent ampoule


Rayzon 20 mg

Powder and solvent for solution for injection






1 ml solvent ampoule contains sodium chloride, hydrochloric acid, sodium hydroxide and waterfor injections.



1 vial and 1 solvent ampoule





58


8. EXPIRY DATE

EXP {MM/YYYY}


There are no special storage instructions.





EU/0/00/000/000


<Batch>/<Lot> {number}





59


OUTER CARTON TEXT: 20 mgPACK SIZE: 3 vials and 3 solvent ampoules


Rayzon 20 mg










3 vials and 3 solvent ampoules


Read the package leaflet before use. Intravenous or intramuscular use



60


8. EXPIRY DATE

EXP {MM/YYYY}


There are no special storage instructions





EU/0/00/000/000


<Batch> <Lot> {number}





61




Rayzon 20 mg
















62

8. EXPIRY DATE

EXP {MM/YYYY}







EU/0/00/000/000







63


SOLVENT AMPOULE TEXT : 1 ml


Sodium chloride 9 mg/ml (0.9%) solution


Solvent for Rayzon 20 mg


3. EXPIRY DATE

<EXP {MM/YYYY}>

4. BATCH NUMBER



1 ml

64


OUTER CARTON: 40 mgPACK SIZE: 10 vials


Rayzon 40 mg









10 vials






65

8. EXPIRY DATE

EXP {MM/YYYY}


There are no special storage precautions.





EU/0/00/000/000







66


VIAL TEXT: 40 mg


Rayzon 40 mg



IV/IM



3. EXPIRY DATE

<EXP {MM/YYYY}>

4. BATCH NUMBER



67


OUTER CARTON: 40 mgPACK SIZE: 1 vial and 1 solvent ampoule


Rayzon 40 mg




Each vial contains 40 mg parecoxib, as 42.36 mg parecoxib sodium. When reconstituted with 2 mlsolvent, provides 20 mg/ml of parecoxib.



2 ml solvent ampoule contains sodium chloride, hydrochloric acid, sodium hydroxide and water forinjections.



1 vial and 1 solvent ampoule






8. EXPIRY DATE

EXP {MM/YYYY}

68







EU/0/00/000/000







69




Rayzon 40 mg
















8. EXPIRY DATE

EXP {MM/YYYY}

70


There are no special storage instructions





EU/0/00/000/000







71




Rayzon 40 mg
















8. EXPIRY DATE

EXP {MM/YYYY}

72







EU/0/00/000/000







73


SOLVENT AMPOULE TEXT : 2 ml


Sodium chloride 9 mg/ml (0.9%) solution


Solvent for Rayzon 40 mg


3. EXPIRY DATE

<EXP {MM/YYYY}>

4. BATCH NUMBER



2 ml

74

B. PACKAGE LEAFLET

75

PACKAGE LEAFLET

Read all of this leaflet carefully before you are given this medicine.- Keep this leaflet. You may need to read it again.- If you have further questions, please ask your doctor or your pharmacist. What’s in this leaflet:1. What Rayzon is and what it’s used for2. Before you are given Rayzon3. How the injection is given4. Possible side effects5. Storing Rayzon6. Other information7. Information for the Health Professional Rayzon 20 mg powder for solution for injection

The active substance in Rayzon is parecoxib 20 mg/vial (as 21.18mg parecoxib sodium). Afterreconstitution the final concentration of parecoxib is 20 mg/ml.Other ingredients are dibasic sodium phosphate heptahydrate; phosphoric acid and/or sodiumhydroxide may have been added for pH adjustment.

Marketing authorisation holder: Pharmacia Europe EEIG, Hillbottom Road, High Wycombe,Buckinghamshire, HP12 4PX, United Kingdom.

Manufacturer: Pharmacia Limited, Whalton Road, Morpeth, Northumberland NE61 3YA, UnitedKingdom. 1. WHAT Rayzon IS AND WHAT IT’S USED FOR Rayzon is a powder for solution for injection. It is supplied in cartons containing 10 glass vials. Rayzon is used to treat pain. The injection is given to you by a doctor or nurse, usually in a hospitalor clinic, such as after an operation. It is one of a family of medicines called COX-2 inhibitors (this isshort for cyclo-oxygenase-2 inhibitors). Pain and swelling are sometimes caused by substances in the body called prostaglandins. Rayzonworks by lowering the amount of these prostaglandins. There are other prostaglandins that protect thestomach lining or cause the blood to clot, and Rayzon does not affect those. 2. BEFORE YOU ARE GIVEN Rayzon You will not be given Rayzon…

� If you are allergic to parecoxib or any of the other ingredients of Rayzon (see blue-shadedarea, below left)

� If you are allergic or have ever had reactions to acetylsalicylic acid or have ever hadreactions to aspirin or similar medicines for pain (ibuprofen, for example). Reactions mightinclude wheezing (bronchospasm), badly blocked nose, itchy skin, rash or swelling of theface, lips or tongue, other allergic reactions or nasal polyps after taking these medicines.

� If you are in your last three months of pregnancy� If you are breast-feeding

76

� If you have severe liver disease.� If you have an active stomach ulcer or bleeding in the stomach or intestines� If you have inflammatory bowel disease� If you have severe congestive heart failure

If any of these applies to you, you will not be given the injection. Tell your doctor immediately.Taking special care with RayzonSome people will need special care from their doctors when they are given Rayzon.Make sure your doctor knows, before you are given Rayzon …

� If you have liver or kidney disease� If you have fluid retention (oedema)� If you have heart failure, high blood pressure, or if you are about to have heart

surgery and have had a stroke� If you might be dehydrated – this may happen if you have had diarrhoea or have been

vomiting (being sick) or unable to drink fluids� If you are being treated for an infection. Rayzon may interfere by masking fever,

which is a sign of infection� If you are a women trying to become pregnant

Pregnant or breast-feeding women� If you are pregnant, tell your doctor, as Rayzon may not be right for you. You will not

be given Rayzon in the last three months of pregnancy.� If you are breast-feeding, you must not have Rayzon. Ask your doctor for advice: it

may be better to stop breast-feeding altogether to take the injections.

Get advice from a doctor or pharmacist before taking any medicine if you’re pregnant or breast-feeding.

Driving or using machinesIf the injection makes you feel dizzy or tired, do not drive or use machines until you feel better again.

Other medicines and RayzonTell your doctor or nurse about any other medicines you are taking or took recently (in the lastweek) – even medicines you bought yourself without a prescription. Medicines can sometimesinterfere with each other. Your doctor may reduce the dose of Rayzon or other medicines, or you mayneed to take a different medicine. It’s especially important to mention:

� Fluconazole – used for fungal infections� ACE inhibitors – used for high blood pressure and heart conditions� Cyclosporin or Tacrolimus – used after transplants� Warfarin – or other medicines used to prevent blood clots� Lithium – used to treat depression.� Rifampicin – used for bacterial infections� Antiarrythmics – used to treat an irregular heartbeat� Phenytoin or Carbamazepine – used for epilepsy� Theophylline – used for asthma� Methotrexate – used for rheumatoid arthritis and cancer� Antidepressants – used to treat depression� Neuroleptics – used to treat psychoses

3. HOW THE INJECTION IS GIVEN Rayzon will be given to you by a doctor or nurse. They will dissolve the powder before giving youthe injection, and will inject the solution into a vein or a muscle. You will only be given Rayzon forshort periods, and only for pain relief.

77

If there are particles in the injection solution or if either the powder or solution is discoloured, theproduct will not be used.

The usual dose to start with is 40 mg.You may be given another dose – either 20 mg or 40 mg – 6 to 12 hoursafter the first one.You will not be given more than 80 mg in 24 hours.

Some people may be given lower doses:� People with liver problems� Patients over 65 who weigh less than 50 kg� People taking fluconazole.

Children and adolescents under the age of 18 will not be given Rayzon. People aged 18 and overwill be given the adult dose. 4. POSSIBLE SIDE EFFECTS

Some people given Rayzon can have side effects. If you notice any of these, or any other effects ofthe injections not mentioned, tell a doctor or nurse.

More common effectsThese could affect between 1 and 10 in every 100 people

� Blood pressure may be made higher or lower� You may get back pain� Ankles, legs and feet may swell (fluid retention)� You may feel numb� You may get stomach ache, indigestion, bloating and wind� Tests may show abnormal kidney function� You may feel agitated or find it hard to sleep� There is a risk of anaemia� You may get a sore throat or difficulty breathing� Your skin may be itchy� You may pass less urine than usual.> If any of these affects you, talk to your doctor or nurse.

Uncommon effectsThese could affect less than 1 in every 100 people

� The heart may beat more slowly� Blood tests may show abnormal liver function� You may bruise easily (or have a low blood platelet count)� Surgical wounds may become infected� There is a risk of stroke.

> If any of these affects you, talk to your doctor or nurse. 5. STORING Rayzon

For Section 5please turn over >


78

Keep out of the reach or sight of children.

The product should not be used after the expiry date stated on the label.

Your doctor will use Rayzon as soon as possible after it is mixed with solvent.If there are particles in the injection solution or if either the powder or solution is discoloured, thesolution will not be used. 6. OTHER INFORMATION For any information about this medicinal product, please contact the local representative of theMarketing Authorisation Holder.

België/Belgique/BelgienPharmacia N.V./S.A.Twin Squares - Culliganlaan 1cB - 1831 DiegemTél/Tel: +32 2 749 50 11

Luxembourg/LuxemburgPharmacia N.V./S.A.Twin Squares - Culliganlaan 1c1831 DiegemBelgique/BelgienTél: +32 2 749 50 11

DanmarkPharmacia ASOvergaden neden Vandet 7DK-1414 Kobenhavn KTlf: + 45 32 96 52 00

NederlandPharmacia B.V.Houttuinlaan 4NL-3447 GM WoerdenTel : +31 348 49 49 49

DeutschlandPharmacia GmbHAm Wolfsmantel 46D-91058 ErlangenTel: +49 0 913 1620

NorgePharmacia Norge ASLilleakerveien 2BN-0283 OsloTlf: +47 24 09 38 00

ΕλλάδαPharmacia Hellas S.A.Kalavriton 2GR-145 64 N. KifisiaΤηλ: +30 1 81 99 000

ÖsterreichPharmacia Austria GesmbHOberlaaer Str. 251A-1101 WeinTel: +43 1 68050-0

EspañaPharmacia Spain, S.A.Ctra de Rubi, 90-100S. Cugat de VallesE-08190 BarcelonaTel: +34 93 582 16 16

PortugalPharmacia Corporation Laboratórios Lda.Av. Do Forte, 3P-2795-505 CarnaxideTel: +351 21 424 9200

FrancePharmacia S.A.S.1 rue Antoine LavoisierF-78280 GuyancourtTél: +33 1 30 64 34 00

Suomi/FinlandPharmacia OyRajatorpantie/Råtorpsvägen 41 CFIN-01640 Vantaa/VandaPuh/Tel: +358 9 852 071

IrelandPharmacia (Ireland) Limited

SverigePharmacia Sverige AB

79

Airways Industrial EstateDublin 17Tel: +353 1 842 8733

SE-112 87 StockholmTel: +46 8 695 8000

ÍslandPharmaco hf.Hörgatúni 2IS-210 GarðabæSími: +354 535 7000

United KingdomPharmacia LimitedDavy AveKnowlhillMilton Keynes MK5 8PHTel: +44 1908 661101

ItaliaPharmacia Italia S.p.A.Via R. Koch 1.2I-20152 MilanoTel: +39 02 48381

This leaflet was last approved on {date}

<----------------------------------------------------------------------------------------------------------------

80

7. INFORMATION FOR THE HEALTH PROFESSIONAL

Administration is by intramuscular (IM) or intravenous (IV) injection. The IM injection is to begiven slowly and deeply into the muscle and the IV bolus injection may be given rapidly and directlyinto a vein or into an existing IV line.This medicinal product must not be mixed with other medicinal products and is to be reconstitutedonly with:

• sodium chloride 9 mg/ml (0.9%) solution• glucose 50 g/l (5%) solution for infusion• sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection

Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium).20 mg vial: Remove the yellow flip-off cap to expose the central portion of the rubber stopper of theparecoxib 20 mg vial. Withdraw, with a sterile needle and syringe, 1 ml of an acceptable solvent andinsert the needle through the central portion of the rubber stopper transferring the solvent into theparecoxib 20 mg vial.Dissolve the powder completely using a gentle swirling motion and inspect the reconstituted productbefore use.The entire contents of the vial should be withdrawn for a single administration.After reconstitution with acceptable solvents, Rayzon may only be injected into IV lines delivering:

• sodium chloride 9 mg/ml (0.9%) solution• glucose 50 g/l (5%) solution for infusion• sodium chloride 4.5 mg/ml (0.45%) and glucose 50 g/l (5%) solution for injection• Ringer-Lactate solution for injection

The reconstituted solution must not be used if discoloured or cloudy or if particulate matter isobserved.The solution is for single use only and must not be stored in a refrigerator or freezer.

81

PACKAGE LEAFLET

Read all of this leaflet carefully before you are given this medicine.- Keep this leaflet. You may need to read it again.- If you have further questions, please ask your doctor or your pharmacist.

What’s in this leaflet:1. What Rayzon is and what it’s used for2. Before you are given Rayzon3. How the injection is given4. Possible side effects5. Storing Rayzon6. Other information7. Information for the Health Professional Rayzon 20 mg powder and solvent for solution for injection


The liquid solvent to dissolve the powder contains sodium chloride and water for injections. Smallamounts of hydrochloric acid or sodium hydroxide may have been added for pH adjustment.


Manufacturer: Pharmacia Limited, Whalton Road, Morpeth, Northumberland NE61 3YA, UnitedKingdom. 1. WHAT Rayzon IS AND WHAT IT’S USED FOR Rayzon is a powder for solution for injection. It is supplied in cartons containing 1, 3 or 5 vials thatalso contain 1, 3 or 5 glass ampoules of a solvent for dissolving the contents of the vials. Rayzon is used to treat pain. The injection is given to you by a doctor or nurse, usually in a hospitalor clinic, such as after an operation. It is one of a family of medicines called COX-2 inhibitors (this isshort for cyclo-oxygenase-2 inhibitors). Pain and swelling are sometimes caused by substances in the body called prostaglandins. Rayzonworks by lowering the amount of these prostaglandins. There are other prostaglandins that protect thestomach lining or cause the blood to clot, and Rayzon does not affect those. 2. BEFORE YOU ARE GIVEN Rayzon You will not be given Rayzon…

� If you are allergic to parecoxib or any of the other ingredients of Rayzon (see blue-shaded area, below left)

� If you are allergic or have ever had reactions to acetylsalicylic acid or have ever hadreactions to aspirin or similar medicines for pain (ibuprofen, for example). Reactions

82

might include wheezing (bronchospasm), badly blocked nose, itchy skin, rash or swellingof the face, lips or tongue, other allergic reactions or nasal polyps after taking thesemedicines.

� If you are in your last three months of pregnancy� If you are breast-feeding� If you have severe liver disease.� If you have an active stomach ulcer or bleeding in the stomach or intestines� If you have inflammatory bowel disease� If you have severe congestive heart failure

If any of these applies to you, you will not be given the injection. Tell your doctor immediately. Taking special care with RayzonSome people will need special care from their doctors when they are given Rayzon.Make sure your doctor knows, before you are given Rayzon …












84












85





Your doctor will use Rayzon as soon as possible after it is mixed with solvent.

If there are particles in the injection solution or if either the powder or solution is discoloured, thesolution will not be used. 6. OTHER INFORMATION For any information about this medicinal product, please contact the local representative of theMarketing Authorisation Holder.

België/Belgique/BelgienPharmacia N.V./S.A.Twin Squares – Culliganlaan 1cB - 1831 DiegemTél/Tel: +32 2 749 50 11










86



IrelandPharmacia (Ireland) LimitedAirways Industrial EstateDublin 17Tel: +353 1 842 8733

SverigePharmacia Sverige ABSE-112 87 StockholmTel: +46 8 695 8000





<----------------------------------------------------------------------------------------------------------------

87




Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium).20 mg vial: Remove the yellow flip-off cap to expose the central portion of the rubber stopper of theparecoxib 20 mg vial. Withdraw, with a sterile needle and syringe, 1 ml of an acceptable solvent andinsert the needle through the central portion of the rubber stopper transferring the solvent into theparecoxib 20 mg vial.Dissolve the powder completely using a gentle swirling motion and inspect the reconstituted productbefore use.The entire contents of the vial should be withdrawn for a single administration.After reconstitution with acceptable solvents, Rayzon may only be injected into IV lines delivering:



88

PACKAGE LEAFLET


What’s in this leaflet:1. What Rayzon is and what it’s used for2. Before you are given Rayzon3. How the injection is given4. Possible side effects5. Storing Rayzon6. Other information7. Information for the Health Professional Rayzon 40 mg powder for solution for injection



Manufacturer: Pharmacia Limited, Whalton Road, Morpeth, Northumberland NE61 3YA, UnitedKingdom. 1. WHAT Rayzon IS AND WHAT IT’S USED FOR Rayzon is a powder for solution for injection. It is supplied in cartons containing 10 glass vials. Rayzon is used to treat pain. The injection is given to you by a doctor or nurse, usually in a hospitalor clinic, such as after an operation. It is one of a family of medicines called COX-2 inhibitors (this isshort for cyclo-oxygenase-2 inhibitors). Pain and swelling are sometimes caused by substances in the body called prostaglandins. Rayzonworks by lowering the amount of these prostaglandins. There are other prostaglandins that protect thestomach lining or cause the blood to clot, and Rayzon does not affect those. 2. BEFORE YOU ARE GIVEN Rayzon You will not be given Rayzon…


� If you are allergic or have ever had reactions to acetylsalicylic acid or have ever hadreactions to aspirin or similar medicines for pain (ibuprofen, for example). Reactions mightinclude wheezing (bronchospasm), badly blocked nose, itchy skin, rash or swelling of theface, lips or tongue, other allergic reactions or nasal polyps after taking these medicines.

� If you are in your last three months of pregnancy� If you are breast-feeding

89

� If you have severe liver disease.� If you have an active stomach ulcer or bleeding in the stomach or intestines� If you have inflammatory bowel disease� If you have severe congestive heart failure

If any of these applies to you, you will not be given the injection. Tell your doctor immediately.Taking special care with RayzonSome people will need special care from their doctors when they are given Rayzon.Make sure your doctor knows, before you are given Rayzon …













90













91



Your doctor will use Rayzon as soon as possible after it is mixed with solvent. If there are particles in the injection solution or if either the powder or solution is discoloured, thesolution will not be used. 6. OTHER INFORMATION For any information about this medicinal product, please contact the local representative of theMarketing Authorisation Holder.













IrelandPharmacia (Ireland) Limited

SverigePharmacia Sverige AB

92

Airways Industrial EstateDublin 17Tel: +353 1 842 8733

SE-112 87 StockholmTel: +46 8 695 8000





<---------------------------------------------------------------------------------------------------------------

93




Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium).40 mg vial: Remove the purple flip-off cap to expose the central portion of the rubber stopper of theparecoxib 40 mg vial. Withdraw, with a sterile needle and syringe, 2 ml of an acceptable solvent andinsert the needle through the central portion of the rubber stopper transferring the solvent into theparecoxib 40 mg vial.Dissolve the powder completely using a gentle swirling motion and inspect the reconstituted productbefore use.The entire contents of the vial should be withdrawn for a single administration.After reconstitution with acceptable solvents, Rayzon may only be injected into IV lines delivering:



94

PACKAGE LEAFLET


What’s in this leaflet:1. What Rayzon is and what it’s used for2. Before you are given Rayzon3. How the injection is given4. Possible side effects5. Storing Rayzon6. Other information7. Information for the Health Professional Rayzon 40 mg powder and solvent for solution for injection


The liquid solvent to dissolve the powder contains sodium chloride and water for injections. Smallamounts of hydrochloric acid or sodium hydroxide may have been added for pH adjustment.


Manufacturer: Pharmacia Limited, Whalton Road, Morpeth, Northumberland NE61 3YA, UnitedKingdom. 1. WHAT Rayzon IS AND WHAT IT’S USED FOR Rayzon is a powder for solution for injection. It is supplied in cartons containing 1, 3 or 5 vials thatalso contain 1, 3 or 5 glass ampoules of a solvent for dissolving the contents of the vials. Rayzon is used to treat pain. The injection is given to you by a doctor or nurse, usually in a hospitalor clinic, such as after an operation. It is one of a family of medicines called COX-2 inhibitors (this isshort for cyclo-oxygenase-2 inhibitors). Pain and swelling are sometimes caused by substances in the body called prostaglandins. Rayzonworks by lowering the amount of these prostaglandins. There are other prostaglandins that protect thestomach lining or cause the blood to clot, and Rayzon does not affect those. 2. BEFORE YOU ARE GIVEN Rayzon You will not be given Rayzon…


� If you are allergic or have ever had reactions to acetylsalicylic acid or have ever hadreactions to aspirin or similar medicines for pain (ibuprofen, for example). Reactions might

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include wheezing (bronchospasm), badly blocked nose, itchy skin, rash or swelling of theface, lips or tongue, other allergic reactions or nasal polyps after taking these medicines.

� If you are in your last three months of pregnancy� If you are breast-feeding� If you have severe liver disease.� If you have an active stomach ulcer or bleeding in the stomach or intestines� If you have inflammatory bowel disease� If you have severe congestive heart failure

If any of these applies to you, you will not be given the injection. Tell your doctor immediately. Taking special care with RayzonSome people will need special care from their doctors when they are given Rayzon.Make sure your doctor knows, before you are given Rayzon …












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Your doctor will use Rayzon as soon as possible after it is mixed with solvent.

If there are particles in the injection solution or if either the powder or solution is discoloured, thesolution will not be used. 6. OTHER INFORMATION For any information about this medicinal product, please contact the local representative of theMarketing Authorisation Holder.











FrancePharmacia S.A.S.1 rue Antoine Lavoisier

Suomi/FinlandPharmacia OyRajatorpantie/Råtorpsvägen 41 C

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F-78280 GuyancourtTél: +33 1 30 64 34 00

FIN-01640 Vantaa/VandaPuh/Tel: +358 9 852 071

IrelandPharmacia (Ireland) LimitedAirways Industrial EstateDublin 17Tel: +353 1 842 8733

SverigePharmacia Sverige ABSE-112 87 StockholmTel: +46 8 695 8000





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Use aseptic technique to reconstitute lyophilised parecoxib (as parecoxib sodium).40 mg vial: Remove the purple flip-off cap to expose the central portion of the rubber stopper of theparecoxib 40 mg vial. Withdraw, with a sterile needle and syringe, 2 ml of an acceptable solvent andinsert the needle through the central portion of the rubber stopper transferring the solvent into theparecoxib 40 mg vial.Dissolve the powder completely using a gentle swirling motion and inspect the reconstituted productbefore use.The entire contents of the vial should be withdrawn for a single administration.After reconstitution with acceptable solvents, Rayzon may only be injected into IV lines delivering:



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